Variant chr11-68312746-C-CGCTGCT details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

The NM_002335.4(LRP5):c.55_60dup(p.Leu19_Leu20dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000929 in 1,061,312 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 28)

Exomes 𝑓: 0.00088 ( 2 hom. )

Consequence

LRP5
NM_002335.4 inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 0.00

Variant links:

Genes affected

LRP5 (HGNC:6697): (LDL receptor related protein 5) This gene encodes a transmembrane low-density lipoprotein receptor that binds and internalizes ligands in the process of receptor-mediated endocytosis. This protein also acts as a co-receptor with Frizzled protein family members for transducing signals by Wnt proteins and was originally cloned on the basis of its association with type 1 diabetes mellitus in humans. This protein plays a key role in skeletal homeostasis and many bone density related diseases are caused by mutations in this gene. Mutations in this gene also cause familial exudative vitreoretinopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

LRP5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP6

Variant 11-68312746-C-CGCTGCT is Benign according to our data. Variant chr11-68312746-C-CGCTGCT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 372405.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

BS2

High Homozygotes in GnomAdExome4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP5	NM_002335.4 linkuse as main transcript	c.55_60dup	p.Leu19_Leu20dup	inframe_insertion	1/23	ENST00000294304.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP5	ENST00000294304.12 linkuse as main transcript	c.55_60dup	p.Leu19_Leu20dup	inframe_insertion	1/23	1	NM_002335.4	P1
LRP5	ENST00000529993.5 linkuse as main transcript	c.55_60dup	p.Leu19_Leu20dup	inframe_insertion, NMD_transcript_variant	1/23	1

Frequencies

GnomAD3 genomes

AF:

0.00126

AC:

182

AN:

144330

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000902

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000888

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0101

Gnomad SAS

AF:

0.00189

Gnomad FIN

AF:

0.000120

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00109

Gnomad OTH

AF:

0.00100

GnomAD3 exomes

AF:

0.000491

AC:

AN:

16308

Hom.:

AF XY:

0.000507

AC XY:

AN XY:

9856

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00102

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000758

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000349

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000878

AC:

805

AN:

916896

Hom.:

Cov.:

AF XY:

0.000892

AC XY:

391

AN XY:

438478

show subpopulations

Gnomad4 AFR exome

AF:

0.000705

Gnomad4 AMR exome

AF:

0.00241

Gnomad4 ASJ exome

AF:

0.000246

Gnomad4 EAS exome

AF:

0.00736

Gnomad4 SAS exome

AF:

0.000728

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000805

Gnomad4 OTH exome

AF:

0.00186

GnomAD4 genome

AF:

0.00125

AC:

181

AN:

144416

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

AN XY:

70312

show subpopulations

Gnomad4 AFR

AF:

0.000900

Gnomad4 AMR

AF:

0.000955

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00974

Gnomad4 SAS

AF:

0.00190

Gnomad4 FIN

AF:

0.000120

Gnomad4 NFE

AF:

0.00109

Gnomad4 OTH

AF:

0.000992

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2022	In-frame duplication of two Leucine amino acids in the signal peptide sequence of LRP5, leading to 11 Leucine repeats; wild-type sequence has 9 Leucine repeats; Published functional studies expressed human LRP5 with different Leucine repeats number (3-Leu to 11-Leu) of signal peptide in HEK293 cells. Luciferase assay showed ~40% reductions in activity of LRP5 with 11-Leu compared to the WT (9-Leu). Moreover, 11-Leu LRP5 had greater retention in the cytoplasmic fraction compared to the WT in western blot assay (Chung et al., 2009); Previosuly reported in German and Turkish control individuals, with a frequency of less than 1%, as compared to 90% frequency of the wild type LRP5 variant with 9 Leucine repeats (Chung et al., 2009); This variant is associated with the following publications: (PMID: 32483926, 34860240, 19177549) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This variant, c.55_60dup, results in the insertion of 2 amino acid(s) of the LRP5 protein (p.Leu19_Leu20dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with LRP5-related conditions (PMID: 32483926, 34860240). ClinVar contains an entry for this variant (Variation ID: 372405). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects LRP5 function (PMID: 19177549). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2023

The c.55_60dupCTGCTG (p.L19_L20dup) alteration is located in exon 1 (coding exon 1) of the LRP5 gene. The alteration consists of an in-frame duplication of 6 nucleotides from position 55 to 60, resulting in the duplication of 2 residues. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Osteogenesis imperfecta

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 14, 2021

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 03, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over